Bridged piperidine derivatives

ABSTRACT

The present invention relates to a compound of formula (I), wherein R 1  is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, lower alkoxy or lower alkoxy substituted by halogen; R may be the same or different, if n=2 or 3; n is 1, 2 or 3; m is 1, 2 or 3; Ar is a five or six membered heteroaryl group, selected from (II), (III), (IV) or (V) wherein R 2  is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen or lower alkoxy; R 3  is hydrogen or halogen; -( ) m - is —(CH 2 ) m — or to pharmaceutically active acid addition salts thereof. The compounds may be used for the treatment of Alzheimer&#39;s disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-in-farct dementia, dementia pugilistica or Down syndrome.

The present invention relates to a compound of formula I,

wherein

-   -   R¹ is hydrogen, lower alkyl, lower alkyl substituted by halogen,        halogen, lower alkoxy or lower alkoxy substituted by halogen;        -   R¹ may be the same or different, if n=2 or 3;    -   n is 1, 2 or 3;    -   m is 1, 2 or 3;    -   Ar is a five or six membered heteroaryl group, selected from

-   -   -   wherein        -   R² is hydrogen, lower alkyl, lower alkyl substituted by            halogen, halogen or lower alkoxy;        -   R³ is hydrogen or halogen;

    -   —( )_(m)— is —(CH₂)_(m)—

    -   or to pharmaceutically active acid addition salts thereof.

Now it has been found that the present compounds of formula I aremodulators of γ-secretase, they may be useful for the treatment orprevention of a disease associated with the deposition of β-amyloid inthe brain, in particular Alzheimer's disease, and other diseases such ascerebral amyloid angiopathy, hereditary cerebral hemorrhage withamyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementiapugilistica and Down syndrome.

Alzheimer's disease (AD) is the most common cause of dementia in laterlife. Pathologically, AD is characterized by the deposition of amyloidin extracellular plaques and intracellular neurofibrillary tangles inthe brain. The amyloid plaques are mainly composed of amyloid peptides(Aβ peptides) which originate from the β-Amyloid Precursor Protein (APP)by a series of proteolytic cleavage steps. Several forms of APP havebeen identified of which the most abundant are proteins of 695, 751 and770 amino acids length. They all arise from a single gene throughdifferential splicing. The Aβ peptides are derived from the same domainof the APP.

Aβ peptides are produced from APP through the sequential action of twoproteolytic enzymes termed β- and γ-secretase. β-Secretase cleaves firstin the extracellular domain of APP just outside of the trans-membranedomain (TM) to produce a C-terminal fragment of APP (CTFβ) containingthe TM- and cytoplasmatic domain. CTFβ is the substrate for γ-secretasewhich cleaves at several adjacent positions within the TM to produce theAβ peptides and the cytoplasmic fragment. Various proteolytic cleavagesmediated by γ-secretase result in Aβ peptides of different chain length,e.g. Aβ38, Aβ40 and Aβ42. The latter one is regarded to be the morepathogenic amyloid peptide because of its strong tendency to formneurotoxic aggregates.

The β-secretase is a typical aspartyl protease. The γ-secretase is ahigh molecular weight complex that consists of four essential subunits:Presenilin (PS, including PS1 and PS2), nicastrin, anterior pharynxdefective 1 (APH-1), and presenilin enhancer 2 (PEN-2). The atomicstructure of human γ-secretase at 3.4 Å resolution has been published(X. Bai, C. Yan, G. Yang, P. Lu, D. Ma, L. Sun, R. Zhou, S. H. W.Scheres, Y. Shi, Nature 2015, 525, pages 212-217. The presenilins arebearing the catalytic site and represent a group of atypical aspartylproteases which cleave their substrates within the TM of and which arethemselves polytopic membrane proteins. The other essential componentsof γ-secretase , nicastrin and the products of the aph1 and pen-2 genesare believed to be responsible for substrate recognition andrecruitment. Proven substrates for γ-secretase are APP and the proteinsof the Notch receptor family, however, γ-secretase has a loose substratespecificity and many further membrane proteins unrelated to APP andNotch have been reported to be cleaved by the γ-secretase in vitro.

The γ-secretase activity is absolutely required for the production of Aβpeptides. This has been shown both by genetic means, i.e., ablation ofthe presenilin genes and by low-molecular-weight inhibitory compounds.According to the amyloid cascade hypothesis for AD the production anddeposition of Aβ is the ultimate cause for the disease. Therefore, itwas believed that selective and potent inhibition of γ-secretase mightbe useful for the prevention and treatment of AD.

An alternative mode of treatment is the modulation of the γ-secretaseactivity which results in a selective reduction of the Aβ42 production.This will lead in an increase of shorter Aβ isoforms, such as Aβ38, Aβ37or others, which have no or reduced capability for aggregation andplaque formation, and are not or less neurotoxic. Compounds which showthis effect on modulating y-secretase activity include certainnon-steroidal anti-inflammatory drugs (NSAIDs) and related analogues(Weggen et al., Nature, 414 (2001) 212-16).

Thus, the compounds of this invention will be useful for the treatmentor prevention of a disease associated with the deposition of β-amyloidin the brain, in particular Alzheimer's disease, and other diseases suchas cerebral amyloid angiopathy, hereditary cerebral hemorrhage withamyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementiapugilistica and Down syndrome.

Numerous documents describe the current knowledge on y-secretasemodulation, for example the following publications:

Morihara et al, J. Neurochem., 83 (2002) 1009-12

Jantzen et al, J.Neuroscience, 22 (2002) 226-54

Takahashi et al, J. Biol. Chem., 278 (2003) 18644-70

Beher et al, J. Biol. Chem. 279 (2004) 43419-26

Lleo et al, Nature Med. 10 (2004) 1065-6

Kukar et al, Nature Med. 11 (2005) 545-50

Perretto et al, J. Med. Chem. 48 (2005) 5705-20

Clarke et al, J. Biol. Chem. 281 (2006) 31279-89

Stock et al, Bioorg. Med. Chem. Lett. 16 (2006) 2219-2223

Narlawar et al, J. Med. Chem. 49 (2006) 7588-91

Ebke et al, J. Biol. Chem., 286 (2011) 37181-86

Oehlich, Gijsen et al, J. Med. Chem., 54 (2011), 669-698

Li et al., Biochemistry, 52, (2013), 3197-3216

Hall et al, Progress in Med. Chem., 53 (2014) 101-145

Bursavich et al, J. Med. Chem., 59 (2016) DOI:10.1021/acs.jmedchem.5b01960

The following definitions for compounds of formula I are used:

As used herein, the term “lower alkyl” denotes a saturated straight- orbranched-chain group containing from 1 to 7 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl andthe like. Preferred alkyl groups are groups with 1-4 carbon atoms.

As used herein, the term “lower alkyl substituted by halogen” denotes analkyl group as defined above, wherein at least one hydrogen atom isreplaced by halogen, for example CF₃, CHF₂, CH₂F, CHFCF₃, CH₂CHF₂,CH₂CH₂F, CH₂C(CH₃)₂CF₃, CH₂CF₂CF₃, CH(CF₃)₂, CH₂CF₃, (CH₂)₂CF₃,(CH₂)₃CF₃, CH(CH₃)CF₃, CF₂CF₃, and the like. The preferred group is CF₃.

The term “lower alkoxy” denotes a lower alkyl group as defined above,which group is connected via an O atom.

The term “lower alkoxy substituted by halogen” denotes a lower alkoxygroup as defined above, wherein at least one hydrogen atom is replacedby halogen.

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

Objects of the present invention are compounds of formula I, the use ofsuch compounds for the preparation of medicaments for the treatment ofAlzheimer's disease, cerebral amyloid angiopathy, hereditary cerebralhemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarctdementia, dementia pugilistica or Down syndrome, their manufacture andmedicaments based on a compound of formula I in accordance with theinvention.

Further objects of the present invention are all forms of optically pureenantiomers, racemates or diastereometric mixtures for compounds offormula I.

One object of the present invention is a compound of formula I-1,

-   -   wherein    -   R¹ is hydrogen, lower alkyl, lower alkyl substituted by halogen,        halogen, lower alkoxy or lower alkoxy substituted by halogen;        -   R¹ may be the same or different, if n=2 or 3;    -   n is 1, 2 or 3;    -   m is 1, 2 or 3;    -   R² is hydrogen, lower alkyl, lower alkyl substituted by halogen,        halogen or lower alkoxy;    -   -( )_(m)- is —(CH₂)_(m)—        -   or a pharmaceutically active acid addition salts thereof,            for example the following compounds

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   N—[(1R,5S,8S)-3-(2-chloro-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine

-   4-[4-(trifluoromethyl)phenyl]-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-[4-(trifluoromethyl)phenyl]-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

-   4-(3-fluoro-4-methyl-phenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine    4-(3,4-difluorophenyl)-N—[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

-   N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3,5-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine    4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3,5-difluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine    or

-   4-(4-methoxyphenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine.

One further object of the present invention is a compound of formula1-2,

-   -   wherein    -   R¹ is hydrogen, lower alkyl, lower alkyl substituted by halogen,        halogen, lower alkoxy or lower alkoxy substituted by halogen;        -   R¹ may be the same or different, if n=2 or 3;    -   n is 1, 2 or 3;    -   m is 1, 2 or 3;    -   R² is hydrogen, lower alkyl, lower alkyl substituted by halogen,        halogen or lower alkoxy;    -   R³ is hydrogen or halogen;    -   -( )_(m)- is —(CH₂)_(m)—

-   or a pharmaceutically active acid addition salts thereof, for    example the following compounds

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine

-   N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

-   4-(3-fluoro-4-methyl-phenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine

-   N-[(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluoro-4-methyl-phenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   N-[(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine    4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

-   N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3,5-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   N-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   N-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine    or

-   N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine.

One object of the present invention is a compound of formula I-3,

-   -   wherein    -   R¹ is hydrogen, lower alkyl, lower alkyl substituted by halogen,        halogen, lower alkoxy or lower alkoxy substituted by halogen;        -   R¹ may be the same or different, if n=2 or 3;    -   n is 1, 2 or 3;    -   m is 1, 2 or 3;    -   R² is hydrogen, lower alkyl, lower alkyl substituted by halogen,        halogen or lower alkoxy;    -   -( )_(m)- is —(CH₂)_(m)—

-   or a pharmaceutically active acid addition salts thereof, for    example the following compounds

-   N-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   N-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

-   N-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

-   4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine    or

-   4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine.

One object of the present invention is a compound of formula I-4,

-   -   wherein    -   R¹ is hydrogen, lower alkyl, lower alkyl substituted by halogen,        halogen, lower alkoxy or lower alkoxy substituted by halogen;        -   R¹ may be the same or different, if n=2 or 3;    -   n is 1, 2 or 3;    -   m is 1, 2 or 3;    -   -( )_(m)- is —(CH₂)_(m)—

or a pharmaceutically active acid addition salts thereof, for examplethe following compounds

-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine    or-   4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine.

Further objects of the present invention are compounds of formulas

-   -   wherein    -   R¹ is hydrogen, lower alkyl, lower alkyl substituted by halogen,        halogen, lower alkoxy or lower alkoxy substituted by halogen;        -   R¹ may be the same or different, if n=2 or 3;    -   n is 1, 2 or 3;    -   Ar is a five or six membered heteroaryl group, selected from

-   -   -   wherein        -   R² is hydrogen, lower alkyl, lower alkyl substituted by            halogen, halogen or lower alkoxy;        -   R³ is hydrogen or halogen;

or pharmaceutically active acid addition salts thereof.

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods known in the art, for example, byprocesses described below, which processes comprise

-   -   a) reacting a compound of formula 9

with a compound of formula 10

to a compound of formula I

wherein the substituents have the meaning as described above, and,

if desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts;

In more detail, compounds of formula I and their intermediates may beprepared by schemes 1-4 and by the description of 50 specific examples.

General Synthesis Schemes General Synthesis of Derivatives of Type Iawith m=1

The preparation of derivatives of general formula Ia with (m=1), wheremade according to the scheme 1. The synthesis of target compoundscommenced by the nucleophilic addition of a commercially availablesubstituted anilines 2 onto the diphenyl cyanocarbonimidate 3 leading tothe intermediates 4 in a good yield. Upon N-alkylation with anelectrophile [2-(2-bromoethoxy)tetrahydropyran] containing a protectedalcohol moiety the compounds 5 were obtained. Upon reaction withhydrazine the corresponding triazoles 6 were obtained. Deprotection ofthe alcohol protected by tetrahydropyran (THP) group under standardacidic conditions afforded 7 in nearly quantitative yield, the alcoholprecursor for the Mitsunobu reaction forming 8. Finally, a Sandmeyerreaction led to the versatiles intermediates bromotriazole 9, which caneasily undergo a Buchwald type reaction with different amines of type 10affording final products of formula Ia.

General Synthesis of Derivatives of Type Ib with m=2

The preparation of derivatives of general formula Ib with (m=2), wheremade according to the scheme 2. The synthesis of target compoundscommenced by the nucleophilic addition of a commercially availablesubstituted anilines 2 onto the diphenyl cyanocarbonimidate 3 leading tothe intermediates 4 in a good yield. Upon N-alkylation with anelectrophile [2-(3-bromopropoxy)tetrahydropyran] containing a protectedalcohol moiety the compounds 11 were obtained. Upon reaction withhydrazine the corresponding triazoles 12 were obtained. Deprotection ofthe alcohol protected by tetrahydropyran (THP) group under standardacidic conditions afforded 13 in nearly quantitative yield, the alcoholprecursor for the Mitsunobu reaction forming 14. Finally, a Sandmeyerreaction led to the versatiles intermediates bromotriazole 15, which caneasily undergo a Buchwald type reaction with different amines of type 10affording final products of formula Ib.

General Synthesis of Derivatives of Type Ic with m=3

The preparation of derivatives of general formula Ic with (m=3), wheremade according to the scheme 3. The synthesis of target compoundscommenced by the nucleophilic addition of a commercially availablesubstituted anilines 2 onto the diphenyl cyanocarbonimidate 3 leading tothe intermediates 4 in a good yield. Upon N-alkylation with anelectrophile [2-(4-bromobutoxy)tetrahydropyran] containing a protectedalcohol moiety the compounds 16 were obtained. Upon reaction withhydrazine the corresponding triazoles 17 were obtained. Deprotection ofthe alcohol protected by tetrahydropyran (THP) group under standardacidic conditions afforded 18 in nearly quantitative yield, the alcoholprecursor for the Mitsunobu reaction forming 19. Finally, a Sandmeyerreaction led to the versatiles intermediates bromotriazole 20, which caneasily undergo a Buchwald type reaction with different amines of type 10affording final products of formula Ic.

General Synthesis of Derivatives 10

Compounds of formula 10 used in schemes 1-3 can be prepared according tothe scheme 4, can be synthesized starting from tert-butylN-[(1S,5R,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate 21 (CAS847862-26-4). The coupling of 21 with heterocyclic halides of generalformula Ar—X can be accomplished under thermal conditions in a solventsuch as ethanol or NMP in the presence of a base such as Et₃N or byusing displacement reactions under catalytic conditions (like e.g.palladium(0) or copper(II) catalysis) to provide compounds of formula22. After deprotection with acid e.g. trifluoro acetic acid compounds offormula 10 were obtained.

The heterocycles halides are either commercial available, known in theliterature so they can be prepared by methods known in the art oralternatively could be prepared as described in the specification.

The compounds were investigated in accordance with the test givenhereinafter.

Description of γ-Secretase Assay Cellular γ-Secretase Assay

Human neuroglioma H4 cells overexpressing human APP695 with the Swedishdouble mutation (K595N/M596L) were plated at 30,000 cells/well/100 μl in96-well plates in IMDM media containing 10% FCS, 0.2 mg/l Hygromycin Band incubated at 37° C., 5% CO₂.

3-4 hr post plating, compounds are a diluted in media and 50 μl is addedas 1.5-fold concentrate to achieve the final concentration. Compoundincubation is performed for 24 hr. Final doses typically range from 4 μMdown to 0.0013 μM in half-log steps resulting in a eight point doseresponse curve.

Appropriate controls using vehicle only and reference compound wereapplied to this assay. The final concentration of Me₂SO was 0.4%.

After incubation at 37° C., 5% CO₂, the supernatant was subjected toquantification of secreted Aβ42 by the means of an AlphaLisa assay kit(Human Amyloid beta 1-42 Kit: Cat # AL203C, Perkin Elmer). 20 μl of thecell culture supernatant was transferred to an assay plate. Then 10 μlof a mixture of the AlphaLisa coupled capture antibody and thebiotinylated detection antibody was added and incubated for 3 hours atroom temperature while softly shaking the assay plate. After a furtheraddition of 20 μl of the Donor beads the assay plate was incubated for30 min at room temperature and constant shaking without exposure todirect light.

The assay plate was then read on a Paradigm AlphaLisa Reader using thebuild-in program with excitation at 680 nm and emission at 570 nm.

The measured signals were then used to calculate IC₅₀ values forinhibition of Aβ42 secretion by nonlinear regression fit analysis usingXLfit 5.3 software (IDBS).

The table below shows the data for all compounds for the inhibition ofAβ42 secretion (nM):

EC₅₀ Aβ42 EC₅₀ Aβ42 Example No. (uM) Example No. (nM) 1 0.0158 26 0.04632 0.0059 27 0.0378 3 0.0264 28 0.0593 4 0.0892 29 0.0233 5 0.0356 300.0320 6 0.0214 31 0.0294 7 0.0302 32 0.0277 8 0.0117 33 0.0404 9 0.019234 0.0144 10 0.0312 35 0.0306 11 0.0278 36 0.0232 12 0.0268 37 0.0344 130.0114 38 0.0402 14 0.0155 39 0.0141 15 0.0306 40 0.0092 16 0.0172 410.0158 17 0.0580 42 0.0406 18 0.0264 43 0.0259 19 0.0139 44 0.0308 200.0231 45 0.0130 21 0.0147 46 0.0103 22 0.0348 47 0.0234 23 0.0233 480.0264 24 0.0804 49 0.0064 25 0.0234 50 0.0570

The compounds of formula I and the pharmaceutically acceptable salts ofthe compounds of formula I can be used as medicaments, e.g. in the formof pharmaceutical preparations. The pharmaceutical preparations can beadministered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatine capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, parenterally, e.g. in the form ofinjection solutions. The administration can also be effected topically,e.g. transdermal administration, or in form of eye drops or ear drops.

The compounds of formula I can be processed with pharmaceutically inert,inorganic or organic carriers for the production of pharmaceuticalpreparations. Lactose, corn starch or derivatives thereof, talc, stearicacids or its salts and the like can be used, for example, as suchcarriers for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carriers for soft gelatine capsules are, for example,vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.Depending on the nature of the active substance no carriers are,however, usually required in the case of soft gelatine capsules.Suitable carriers for the production of solutions and syrups are, forexample, water, polyols, glycerol, vegetable oil and the like. Suitablecarriers for suppositories are, for example, natural or hardened oils,waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

Medicaments containing a compound of formula I or a pharmaceuticallyacceptable salt thereof and a therapeutically inert carrier are also anobject of the present invention, as is a process for their production,which comprises bringing one or more compounds of formula I and/orpharmaceutically acceptable acid addition salts and, if desired, one ormore other therapeutically valuable substances into a galenicaladministration form together with one or more therapeutically inertcarriers.

In accordance with the invention compounds of formula I as well as theirpharmaceutically acceptable salts are useful in the control orprevention of illnesses based on the inhibition of Aβ42 secretion, suchas of Alzheimer's disease.

The dosage can vary within wide limits and will, of course, have to beadjusted to the individual requirements in each particular case. In thecase of oral administration the dosage for adults can vary from about0.01 mg to about 1000 mg per day of a compound of general formula I orof the corresponding amount of a pharmaceutically acceptable saltthereof. The daily dosage may be administered as single dose or individed doses and, in addition, the upper limit can also be exceededwhen this is found to be indicated.

Tablet Formulation (Wet Granulation) mg/tablet Item Ingredients 5 25 100500 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous DTG 125105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 3030 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831

Manufacturing Procedure

-   1. Mix items 1, 2, 3 and 4 and granulate with purified water.-   2. Dry the granules at 50° C.-   3. Pass the granules through suitable milling equipment.-   4. Add item 5 and mix for three minutes; compress on a suitable    press.

Capsule Formulation mg/capsule Item Ingredients 5 25 100 500 1. Compoundof formula I 5 25 100 500 2. Hydrous Lactose 159 123 148 — 3. CornStarch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5Total 200 200 300 600

Manufacturing Procedure

-   1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.-   2. Add items 4 and 5 and mix for 3 minutes.-   3. Fill into a suitable capsule.

Experimental Part

The following examples are provided for illustration of the invention.They should not be considered as limiting the scope of the invention,but merely as being representative thereof.

General

Analytical Methods

HPLC (method LCMS_fastgradient)

Column: Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2.1×30 mm,1.8 μm, Part.no. 959731-902

Solvent A: Water 0.01% Formic Acid; Solvent B: acetonitrile (MeCN)

Gradients:

Time [min] Flow Rate [ml/min] % A % B Initial 0.8 97 3 0.2 1.0 97 3 1.71.0 3 97 2.0 1.0 3 97 2.1 1.0 97 3

Abbreviations

The following abbreviations were used in the experimental part:

-   THF=tetrahydrofurane;-   TBME=methyl-tert-butylether;-   DMF=dimethylformamide;-   TLC=thin layer chromatography;-   RT=room temperature, 20-25° C.

Preparation of Intermediates

Intermediates of type 9 (according to scheme 1)

Intermediate 9-1:

2-bromo-4-(3,4-difluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole

Step 1: 3,4-Difluoroaniline (3.00 g, 23.20 mmol) and diphenylcyanocarbonimidate (5.53 g, 23.20 mmol) were dissolved in 2-propanol(64.00 mL). The reaction mixture was stirred at RT overnight. The crudewas evaporated in vacuo and purified by column chromatography(Hept:EtOAc 100:0 to 50:50) to afford (Z)-phenylN′-cyano-N-(3,4-difluorophenyl) carbamimidate as a white solid (5.00 g,79%). MS (ES+) m/z: 274.1 [M+H]⁺.

Step 2: A solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (5.74 g, 4.15mL, 27.40 mmol), (Z)-phenyl N′-cyano-N-(3,4-difluorophenyl)carbamimidate(5.00 g, 18.30 mmol) and K₂CO₃ (5.06 g, 36.60 mmol) in DMF (180 mL) washeated at 85° C. overnight. An extra amount of2-(2-bromoethoxy)tetrahydro-2H-pyran (5.74 g, 4.15 mL, 27.40 mmol) andK₂CO₃ (5.06 g, 36.60 mmol) were added and the reaction stirred at 100°C. for a further 8 hours and then at 75° C. overnight. The reactionmixture was cooled down to RT, poured onto a saturated aqueous solutionof NH₄Cl and the product extracted three times with EtOAc. The organiclayers were combined, washed with water and then with brine, dried oversodium sulfate, filtered and evaporated in vacuo. The residue was thenpurified by column chromatography using (Hept:EtOAc 100:0 to 70:30) toafford (Z)-phenylN′-cyano-N-(3,4-difluorophenyl)-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)carbamimidateas a yellow oil (1.75 g, 24%). MS (ES+) m/z: 402.2 [M+H]⁺.

Step 3: To a solution of (Z)-PhenylN′-cyano-N-(3,4-difluorophenyl)-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)carbamimidate (1.75 g, 4.36 mmol) in methanol (12 mL) was addedhydrazine hydrate 25% in H₂O (873 mg, 864.00 μl, 4.36 mmol). Thereaction mixture was stirred at 35° C. for 1 hour and then evaporated invacuo to giveN3-(3,4-Difluorophenyl)-N3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-4H-1,2,4-triazole-3,5-diamine(1.79 g, 91%) which was used directly for the next step without furtherpurification. (1.79 g, 91%). MS (ES+) m/z: 340.2 [M+H]⁺.

Step 4: The crude ofN3-(3,4-difluorophenyl)-N3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-4H-1,2,4-triazole-3,5-diamine(1.79 g, 5.27 mmol) was dissolved in a mixture of aqueous HCl 2M (9 mL)an methanol (43 mL). The reaction mixture was stirred at RT for 1 hourand concentrated in vacuo. The residue was diluted with EtOAc and washedwith an aqueous NaHCO₃ solution. The organic layer was dried Na₂SO₄ andthe product purified by combiflash chromatography (CH₂Cl₂:MeOH 100:0 to90:10) to afford2-((5-Amino-4H-1,2,4-triazol-3-yl)(3,4-difluorophenyl)amino)ethanol as awhite solid (0.39 g, 29%). MS (ES+) m/z: 256.2 [M+H]⁺.

Step 5: To a THF (4 mL) solution of2-((5-Amino-4H-1,2,4-triazol-3-yl)(3,4-difluorophenyl) amino)ethanol(50.00 mg, 196 μmol) and triphenylphosphine (154 mg, 588 μmol) was addedDEAD (70 mg, 64 μl, 392 μmol) the reaction was stirred at RT for 24hours. The reaction was stirred for further 7 hours at 50° C. and thenone extra amount of triphenylphosphine (154 mg, 588 μmol), DEAD (70 mg,64 μl, 392 μmol) and THF (4 mL) were added. The reaction mixture wasleft to stir at RT overnight. The mixture was diluted with EtOAc andwashed three times with water and brine; the organic phase was driedover sodium sulfate, filtered and evaporated in vacuo. The crude waspurified using combiflash chromatography (CH₂Cl₂:MeOH 100:0 to 90:10) toafford4-(3,4-difluorophenyl)-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazol-2-amineas a white solid (7.2 mg, 15%). MS (ES+) m/z: 238.1 [M+H]⁺.

Step 6: tert-Butyl nitrile (232 mg, 268 μl, 2.0 mmol) and cupric bromide(452 mg, 96 μl, 2.0 mmol) were combined in CH₃CN (40 mL) and stirred at60° C. before a solution of4-(3,4-difluorophenyl)-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazol-2-amine(140 mg, 590 μmol) in CH₃CN (40 mL) was added drop wise. The reactionmixture was stirred at 75° C. for 2 hours, concentrated in vacuo,diluted with 1M HCl and extracted three times with EtOAc. The combinedorganic layer was dried over sodium sulfate, filtered and evaporated invacuo. The crude was purified by combiflash chromatography (Hept:EtOAc100:0 to 50:50) to afford2-bromo-4-(3,4-difluorophenyl)-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole(0.12 g, 69%) as an off-white solid. MS (ES+) m/z: 301.0 and 303.0[M+H]⁺. (Br isotopes).

Intermediate 9-2:

2-bromo-4-[4-(trifluoromethyl)phenyl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazole

In analogy to the preparation of the intermediate 9-1, starting from4-(trifluoromethyl)aniline was prepared 0.12 g of the intermediate2-bromo-4-[4-(trifluoromethyl)phenyl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazole (9-2) as a white solid. MS (ES+) m/z:333.0 and 335.0 [M+H]⁺. (Br isotopes)

Intermediate 9-3:

2-bromo-4-(2,3,4-trifluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole

In analogy to the preparation of the intermediate 9-1, starting from2,3,4-trifluoroaniline was prepared 0.12 g of the intermediate2-bromo-4-(2,3,4-trifluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole(9-3) as a white solid. MS (ES+) m/z: 319.0 and 321.0 [M+H]⁺. (Brisotopes)

Intermediates of Type 15

Intermediate 15-1:

2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

Step 1: 3,4-Difluoroaniline (3.00 g, 23.20 mmol) and diphenylcyanocarbonimidate (5.53 g, 23.20 mmol) were dissolved in 2-propanol(64.00 mL). The reaction mixture was stirred at RT overnight. The crudewas evaporated in vacuo and purified by column chromatography(Hept:EtOAc 100:0 to 50:50) to afford (Z)-phenylN′-cyano-N-(3,4-difluorophenyl) carbamimidate as a white solid (5.00 g,79%). MS (ES+) m/z: 274.1 [M+H]⁺.

Step 2: A solution of (Z)-phenylN′-cyano-N-(3,4-difluorophenyl)carbamimidate (17.69 g, 64.70 mmol),2-(3-bromopropoxy)tetrahydro-2H-pyran (22.80 g, 17.10 mL, 97.10 mmol)and K₂CO₃ (17.90 g, 129.00 mmol) in DMF (200 mL) was heated overnight at85° C. The reaction mixture was concentrated in vacuo and the residuewas purified by column chromatography (Hept:EtOAc 90:10 to 50:50) togive3-cyano-1-(3,4-difluorophenyl)-2-phenyl-1-(3-tetrahydropyran-2-yloxypropyl)isoureaas a white solid (26.90 g, 49%). MS (ES+) m/z: 416.2 [M+H]⁺.

Step 3: To a solution of of (Z)-phenylN′-cyano-N-(3,4-difluorophenyl)-N-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)carbamimidate(10.20 g, 24.60 mmol) in MeOH (70 mL) was added hydrazine hydrate 25% inwater (4.92 g, 4.87 mL, 24.60 mmol). The reaction mixture was stirred atRT overnight, evaporated and purified by column chromatography(CH₂Cl₂:MeOH 99:1 to 92.5:7.5) to affordN3-(3,4-difluorophenyl)-N3-(3-tetrahydropyran-2-yloxypropyl)-4H-1,2,4-triazole-3,5-diamineas a colourless foam (8.68 g, 78%). MS (ES+) m/z: 354.2 [M+H]⁺.

Step 4: To a solution ofN3-(3,4-difluorophenyl)-N3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-4H-1,2,4-triazole-3,5-diamine(6.75 g, 19.10 mmol) in MeOH (150 mL) followed by addition of aqueousHCl 2M (30 mL). The reaction mixture was stirred at RT for 90 minutesand concentrated in vacuo. The residue was diluted with EtOAc and washedwith an aqueous NaHCO₃ solution. The organic layer was dried on Na₂SO₄and the product purified by combiflash chromatography to afford3-(N-(5-Amino-4H-1,2,4-triazol-3-yl)-3,4-difluoro-anilino)propan-1-ol asa white solid (5.14 g, 95%). MS (ES+) m/z: 270.1 [M+H]⁺.

Step 5: To a solution of3-((5-amino-4H-1,2,4-triazol-3-yl)(3,4-difluorophenyl)amino) propan-1-ol(4.55 g, 16.90 mmol) in DMF (90 mL) at −15/−20° C., was addedtriphenylphosphine (6.65 g, 25.30 mmol). The mixture was stirred at−15/−20° C. for 15 minutes, then at −30° C., DEAD (4.55 g, 4.10 ml,25.30 mmol) was added drop wise over of 20 minutes. The mixture wasstirred at −30° C. for 90 minutes. Water was added to the reactionmixture and then concentrated under vacuo, and the product extractedwith EtOAc. The combined organic layers were washed once with brine,dried over sodium sulfate, filtered and evaporated in vacuo. The crudewas purified using silica chromatography (CH₂Cl₂:MeOH 99:1 to 96:4) toafford4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineas a white solid (3.41 g, 80%). MS (ES+) m/z: 252.1 [M+H]⁺.

Step 6: To a black solution of tert-butyl nitrite (1.01 g, 1.17 mL, 8.86mmol) and cupric bromide (1.98 g, 420 μl, 8.86 mmol) in CH₃CN (150 mL)at 60° C.,4-(3,4-difluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine(1.63 g, 5.90 mmol,) in 50 mL CH₃CN was added drop wise. After addition,the reaction mixture was heated to 75° C. and stirred for 30 minutes.The reaction mixture was concentrated in vacuo, diluted with 2 mL of 1MHCl and extracted 3 times with EtOAc. The organic layers were dried oversodium sulfate and concentrated. The crude was purified bychromatography (CH₂Cl₂:MeOH 99.5:0.5) to afford2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidineas a light yellow solid (1.86 g, 82%). MS (ES+) m/z: 315.0 and 317.0[M+H]⁺. (Br isotopes).

Intermediate 15-2:

2-bromo-4-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from4-(trifluoromethyl)aniline was prepared 32 mg of the intermediate2-bromo-4-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-2) as a white solid. MS (ES+) m/z: 347.0 and 349.0 [M+H]⁺. (Brisotopes).

Intermediate 15-3:

2-bromo-4-(3,5-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from3,5-difluoroaniline was prepared 234 mg of the intermediate2-bromo-4-(3,5-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazlo[1,5-a]pyrimidine(15-3) as a white solid. MS (ES+) m/z: 315.0 and 317.0 [M+H]⁺. (Brisotopes).

Intermediate 15-4:

2-bromo-4-(3-fluoro-4-methyl-phenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from3-fluoro-4-methyl-aniline was prepared 662 mg of the intermediate2-bromo-4-(3-fluoro-4-methyl-phenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-4) as a light yellow oil. MS (ES+) m/z: 311.0 and 313.0 [M+H]⁺. (Brisotopes).

Intermediate 15-5:

2-bromo-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from2,3,4-trifluoroaniline was prepared 134 mg of the intermediate2-bromo-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-5) as a light brown solid. MS (ES+) m/z: 333.0 and 335.0 [M+H]⁺. (Brisotopes).

Intermediate 15-6:

2-bromo-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from3-fluoroaniline was prepared 210 mg of the intermediate2-bromo-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-6) as a light yellow solid. MS (ES+) m/z: 297.0 and 299.0 [M+H]⁺.(Br isotopes).

Intermediate 15-7:

2-bromo-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from4-fluoroaniline was prepared 1.11 g of the intermediate2-bromo-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-7) as a light yellow solid. MS (ES+) m/z: 297.0 and 299.0 [M+H]⁺.(Br isotopes).

Intermediate 15-8:

2-bromo-4-(3-chlorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from3-chloroaniline was prepared 1.06 g of the intermediate2-bromo-4-(3-chlorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-8) as a white solid. MS (ES+) m/z: 313.0 and 315.0 [M+H]⁺. (Brisotopes).

Intermediate 15-9:

2-bromo-4-(2-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from2-fluoroaniline was prepared 1.05 g of the intermediate2-bromo-4-(2-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-9) as a white solid. MS (ES+) m/z: 297.1 and 299.1 [M+H]⁺. (Brisotopes).

Intermediate 15-10:

2-bromo-4-[2-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from2-(trifluoromethyl)aniline was prepared 0.90 g of the intermediate2-bromo-4-[2-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-10) as a white solid. MS (ES+) m/z: 347.1 and 349.1 [M+H]⁺. (Brisotopes).

Intermediate 15-11:

2-bromo-4-(4-chlorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from4-chloroaniline was prepared 1.2 g of the intermediate2-bromo-4-(4-chlorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-11) as a white solid. MS (ES+) m/z: 313.1 and 315.1 [M+H]⁺. (Brisotopes).

Intermediate 15-12:

2-bromo-4-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting fromaniline was prepared 240 mg of the intermediate2-bromo-4-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine (15-12)as a white solid. MS (ES+) m/z: 279.0 and 281.0 [M+H]⁺. (Br isotopes).

Intermediate 15-13:

2-bromo-4-(4-methoxyphenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from4-methoxyaniline was prepared 1.05 g of the intermediate2-bromo-4-(4-methoxyphenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-13) as a white solid. MS (ES+) m/z: 309.1 and 311.1 [M+H]⁺. (Brisotopes).

Intermediate 15-14:

2-bromo-4-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from4-(trifluoromethoxy)aniline was prepared 1.10 g of the intermediate2-bromo-4-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-14) as a white solid. MS (ES+) m/z: 363.1 and 365.1 [M+H]⁺. (Brisotopes).

Intermediate 15-15:

2-bromo-4-(2-chlorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine

In analogy to the preparation of the intermediate 15-1, starting from2-chloroaniline was prepared 1.06 g of the intermediate2-bromo-4-(2-chlorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-15) as a white solid. MS (ES+) m/z: 313.0 and 315.0 [M+H]⁺. (Brisotopes).

Intermediates of Type 20

Intermediate 20-1:

2-bromo-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine

Step 1: 3,4-Difluoroaniline (3.00 g, 23.20 mmol) and diphenylcyanocarbonimidate (5.53 g, 23.20 mmol) were dissolved in 2-propanol(64.00 mL). The reaction mixture was stirred at RT overnight. The crudewas evaporated in vacuo and purified by column chromatography(Hept:EtOAc 100:0 to 50:50) to afford (Z)-phenylN′-cyano-N-(3,4-difluorophenyl) carbamimidate as a white solid (5.00 g,79%). MS (ES+) m/z: 274.1 [M+H]⁺.

Step 2: A solution of (Z)-phenylN′-cyano-N-(3,4-difluorophenyl)carbamimidate (10.0 g, 36.6 mmol),2-(3-bromobutoxy)tetrahydro-2H-pyran (13.30 g, 54.90 mmol) and K₂CO₃(10.10 g, 73.20 mmol) in DMF (350 mL) was heated overnight at 85° C. Thereaction mixture was concentrated in vacuo and the residue was purifiedby column chromatography (Hept:EtOAc 90:10 to 50:50) to give3-cyano-1-(3,4-difluorophenyl)-2-phenyl-1-(4-tetrahydropyran-2-yloxybutyl)isoureaas a colorless oil (5.31 g, 34%). MS (ES+) m/z: 430.2 [M+H]⁺.

Step 3: To a solution of3-cyano-1-(3,4-difluorophenyl)-2-phenyl-1-(4-tetrahydropyran-2-yloxybutyl)isourea(5.29 g, 12.30 mmol) in MeOH (40 mL) was added hydrazine hydrate 25% inwater (2.47 g, 2.44 mL, 12.30 mmol). The reaction mixture was stirred atRT for 7 hours, evaporated and purified by column chromatography(CH₂Cl₂:MeOH 99:1 to 92.5:7.5) to affordN3-(3,4-difluorophenyl)-N3-(3-tetrahydropyran-2-yloxybutyl)-4H-1,2,4-triazole-3,5-diamineas a colourless oil (3.54 g, 78%). MS (ES+) m/z: 368.2 [M+H]⁺.

Step 4: To a solution ofN3-(3,4-difluorophenyl)-N3-(3-tetrahydropyran-2-yloxybutyl)-4H-1,2,4-triazole-3,5-diamine(3.50 g, 9.53 mmol) in MeOH (85 mL) was added an aqueous HCl 2M solution(17 mL). The reaction mixture was stirred at RT for 90 minutes andconcentrated in vacuo. The residue was diluted with EtOAc and washedwith an aqueous NaHCO₃ solution. The organic layer was dried on Na₂SO₄and the product purified by combiflash chromatography to afford4-(N-(5-amino-4H-1,2,4-triazol-3-yl)-3,4-difluoro-anilino)butan-1-ol asa white solid (2.51 g, 93%). MS (ES+) m/z: 284.1 [M+H]⁺.

Step 5: At 0° C., cyanomethylenetrimethylphosphorane 0.5 M in THF (8.47mL, 4.24 mmol) was added drop wise within 15 minutes to a solution of4-((5-amino-4H-1,2,4-triazol-3-yl)(3,4-difluorophenyl)amino)butan-1-ol(1.00 g, 3.53 mmol) in THF (120 mL) at 0° C. and stirred at RTovernight. The mixture was concentrated under vacuo, and the crudediluted with EtOAc and washed with water. The organic layer was driedover sodium sulfate, filtered and evaporated in vacuo. The crude waspurified using silica chromatography (CH₂Cl₂:MeOH 99:1 to 96:4) toafford4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amineas a white solid (0.2 g, 21%). MS (ES+) m/z: 266.1 [M+H]⁺.

Step 6: To a black solution of tert-butyl nitrite (115 mg, 0.13 mL, 1.01mmol) and cupric bromide (225 mg, 47.7 μl, 1.01 mmol) in CH₃CN (15 mL)at 60° C.,4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine(178 mg, 0.671 mmol,) in 25 mL CH₃CN was added drop wise. Afteraddition, the reaction mixture was heated to 75° C. and stirred for 30minutes. The reaction mixture was concentrated in vacuo, diluted with 2mL of 1M HCl and extracted 3 times with EtOAc. The organic layers weredried over sodium sulfate and concentrated. The crude was purified bychromatography (CH₂Cl₂:MeOH 99.5:0.5) to afford2-bromo-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepineas a light yellow oil (0.13 g, 58%). MS (ES+) m/z: 329.0 and 331.0[M+H]⁺. (Br isotopes).

Intermediate 20-2:

2-bromo-4-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine

In analogy to the preparation of the intermediate 20-1, starting from4-(trifluoromethyl)aniline was prepared 72 mg of the intermediate2-bromo-4-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine(20-2) as a white solid. MS (ES+) m/z: 361.0 and 363.0 [M+H]⁺. (Brisotopes).

Intermediates of Type 10

Intermediate 10-1:

(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine

Step 1: In a sealed tube tert-butylN-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate (500 mg, 2.21mmol) was dissolved in EtOH (10 mL) and 4-chloro-6-methylpyrimidine (869mg, 6.63 mmol) was added followed by triethylamine (894 mg, 1.23 mL,8.84 mmol). The reaction mixture was stirred at 130° C. overnight. Thecrude reaction mixture was concentrated in vacuum. The residue wasdiluted with 20 mL of CH₂Cl₂ and 20 mL of water. The organic phase wasextracted with CH₂Cl₂ (3×20 mL), dried over MgSO₄ and concentrated invacuum. The crude material was purified by flash chromatography (0% to100% EtOAc in heptane) to afford tert-butylN-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamateas a yellow solid (496 mg, 71% yield). MS (ES+) m/z: 319.2 [(M+H)⁺].

Step 2: To a light yellow solution of tert-butylN-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(260 mg, 817 μmol) in CH₂Cl₂ (8 mL) was added TFA (931 mg, 629 μl, 8.17mmol). The reaction mixture was stirred at room temperature over nightand concentrated in vacuum. The crude material was purified byIon-exchange column (Si-SCX-2, 10 g, washed with MeOH and liberated withMeOH (NH₃ 2M)) to afford(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine10-1 (195 mg, 804 μmol, 98.5% yield) that was used in the next stepwithout further purification. MS (ES+) m/z: 219.2 [(M+H)⁺]

Intermediate 10-2:

(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine

Step 1: In analogy to the preparation of the intermediate 10-1 (step 1)from tert-butyl N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(200 mg, 884 μmol) and 4-chloro-5-fluoro-6-methylpyrimidine (194 mg,1.33 mmol) in a sealed tube at 100° C. and EtOH as solvent in thepresence of triethylamine (358 mg, 493 μl, 3.53 mmol), tert-butylN-[(1R,5S,8S5)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamatewas obtained as a white solid (255 mg, 758 μmol, 86% yield). MS (ES+)m/z: 337.3 [(M+H)⁺].

Step 2: In analogy to the preparation of intermediate 10-1 (step 2) fromtert-butylN-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(253 mg, 752 μmol) in CH₂Cl₂ in the presence of aqueuous HCl 37% (445mg, 371 μl, 4.51 mmol),(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(170 mg, 719 μmol, 96% yield) was obtained as a white solid and useddirectly in the next step without further purification. MS (ES+) m/z:237.1 [(M+H)⁺].

Intermediate 10-3:

(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine

Step 1: In analogy to the preparation of the intermediate 10-1 (step 1)from tert-butyl N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(250 mg, 1.1 mmol) and 4-chloro-6-fluoro-pyrimidine (220 mg, 1.66 mmol)in a sealed tube at 100° C. using EtOH as solvent in the presence oftriethylamine (447 mg, 616 μl, 4.42 mmol), tert-butylN-[(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(329 mg, 88% yield) was obtained as a white solid. MS (ES+) m/z: 339.2[(M+H)⁺].

Step 2: In analogy to the preparation of intermediate 10-1 (step 2) fromtert-butylN-[(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(325 mg, 959 μmol) in CH₂Cl₂ in the presence of HCl 37% (567 mg, 473 μl,5.76 mmol),(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(230 mg, 100% yield) was obtained as a white solid and used directly inthe next step without further purification. MS (ES+) m/z: 239.2[(M+H)⁺].

Intermediate 10-4:

(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine

Step 1: In analogy to the preparation of the intermediate 10-1 (step 1)from tert-butyl N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(250 mg, 1.1 mmol) and 4-iodo-6-methoxypyrimidine (391 mg, 1.66 mmol) ina sealed tube at 100° C. using DMF as solvent in the presence of K₂CO₃(458 mg, 3.31 mmol), tert-butylN-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(315 mg, 85% yield) was obtained as a white solid. MS (ES+) m/z: 335.2[(M+H)⁺].

Step 2: In analogy to the preparation of intermediate 10-1 (step 2) fromtert-butylN-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(330 mg, 987 μmol) in CH₂Cl₂ in the presence of TFA (1.13 g, 760 μl,9.87 mmol),(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(222 mg, 96% yield) was obtained as a white solid and used directly inthe next step without further purification. MS (ES+) m/z: 235.2[(M+H)⁺].

Intermediate 10-5:

(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine

Step 1: In analogy to the preparation of the intermediate 10-1 (step 1)from tert-butyl N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(1.57 g, 6.87 mmol) and 4-iodo-2-(trifluoromethyl)pyridine (1.5 g, 5.33mmol) in a sealed tube at 150° C. using NMP as solvent in the presenceof DIPEA (964 mg, 1.3 ml, 7.46 mmol), tert-butylN-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]carbamate(1.37 g, 70% yield) was obtained as a white solid. MS (ES+) m/z: 372.2[(M+H)⁺].

Step 2: In analogy to the preparation of intermediate 10-1 (step 2) fromtert-butylN-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]carbamate(1.05 g, 2.82 mmol) in CH₂Cl₂ in the presence of HCl 37% (1.68 g, 1.4mL, 17 mmol),(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine(735 mg, 96% yield) was obtained as a white solid and used directly inthe next step without further purification. MS (ES+) m/z: 272.2[(M+H)⁺].

Intermediate 10-6:

(1R,5S,8S)-3-(2-chloro-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-amine

Step 1: In analogy to the preparation of the intermediate 10-1 (step 1)from tert-butyl N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(120 mg, 0.53 mmol) and 2-chloro-4-fluoro-pyridine (76 mg, 0.58 mmol) ina sealed tube at 150° C. using NMP as solvent in the presence of DIPEA(137 mg, 0.185 ml, 1.06 mmol), tert-butylN-[(1R,5S,8S)-3-(2-chloro-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(150 mg, 82% yield) was obtained as a white solid. MS (ES+) m/z: 338.2[(M+H)⁺].

Step 2: In analogy to the preparation of intermediate 10-1 (step 2) fromtert-butylN-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]carbamate(147 mg, 435 μmol) in CH₂Cl₂ in the presence of HCl 37% (257 mg, 214 μl,2.61 mmol),(1R,5S,8S)-3-(2-chloro-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-amine (90mg, 87% yield) was obtained as a white solid and used directly in thenext step without further purification. MS (ES+) m/z: 238.1 [(M+H)⁺].

Intermediate 10-7:

(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-amine

Step 1: In analogy to the preparation of the intermediate 10-1 (step 1)from tert-butyl N-[(1R,55,85)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(2.00 g, 8.84 mmol) and 4-fluoro-2-methoxypyridine (1.12 g, 8.84 mmol)in a sealed tube at 140° C. using NMP as solvent in the presence ofDIPEA (2.28 g, 3.09 mL, 17.70 mmol), tert-butylN-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(1.42 g, 48%) was obtained as a white solid. MS (ES+) m/z: 334.3[(M+H)⁺].

Step 2: In analogy to the preparation of intermediate 10-1 (step 2) fromtert-butylN-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(1.42 g, 4.26 mmol) in CH₂Cl₂ in the presence of TFA (7.38 g, 5.0 mL,15.2 mmol),(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-amine(0.89 g, 89%) was obtained as a white solid and used directly in thenext step without further purification. MS (ES+) m/z: 234.2 [(M+H)⁺].

Intermediate 10-8:

(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine

Step 1: In analogy to the preparation of the intermediate 10-1 (step 1)from tert-butyl N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(2.00 g, 8.84 mmol) and 3,5-dichloropyridazine (2.0 g, 13.4 mmol) in asealed tube at 90° C. using EtOH as solvent in the presence of Et₃N(3.63 g, 5.0 mL, 35.9 mmol), tert-butylN-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(1.71 g, 54%) was obtained as a white solid. MS (ES+) m/z: 339.2[(M+H)⁺].

Step 2: In analogy to the preparation of intermediate 10-1 (step 2) fromtert-butylN-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(0.93 g, 2.72 mmol) in CH₂Cl₂ in the presence of HCl 37% (1.61 g, 1.34mL, 16.3 mmol),(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(0.65 g, 100%) was obtained as a white solid and used directly in thenext step without further purification. MS (ES+) m/z: 239.1 [(M+H)⁺].

Intermediate 10-9:

(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine

Step 1: To a solution of tert-butylN-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(963 mg, 2.70 mmol) in MeOH (22 mL) in a sealed tube was added amethanol solution of NaOMe (25%, 1.9 mL, 8.3 mmol). The reaction mixturewas heated at 85° C. over night. The reaction mixture was adsorbed onIsolute HM-N and a column chromatography gave tert-butylN-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(362 mg, 38%) as a white solid. MS (ES+) m/z: 335.2 [(M+H)⁺].

Step 2: In analogy to the preparation of intermediate 10-1 (step 2) fromtert-butylN-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate(0.93 g, 2.72 mmol) in CH₂Cl₂ in the presence of TFA (1.12 g, 0.76 mL,9.86 mmol),(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(225 mg, 96%) was obtained as a white solid and used directly in thenext step without further purification. MS (ES+) m/z: 235.2 [(M+H)⁺].

Intermediate 10-10:

(1R,5S,8S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-amine

Step 1: To a light yellow solution of tert-butylN-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate (250 mg, 1.1 mmol), in EtOH (4 mL) was added sodiumbicarbonate (102 mg, 1.22 mmol) followed by cyanogen bromide (129 mg,1.22 mmol). The reaction was stirred over night at room temperature andthe suspension was filtered off and washed with some EtOH. The crudereaction mixture was concentrated in vacuum and the residue was purifiedby flash chromatography (silica gel, 12 g, 0% to 100% EtOAc in heptane)to afford tert-butylN-[(1R,5S,8S)-3-cyano-3-azabicyclo[3.2.1]octan-8-yl]carbamate as a lightyellow solid (216 mg, 78%). MS (ES+) m/z: 252.2 [(M+H)⁺].

Step 2: Tert-butylN-[(1R,5S,8S)-3-cyano-3-azabicyclo[3.2.1]octan-8-yl]carbamate (200 mg,796 μmol) was dissolved in EtOH (20 mL) and N-hydroxyacetimidamide((70.7 mg, 955 μmol) and zinc chloride ((130 mg, 955 μmol) were added.The reaction mixture was stirred at room temperature for 2 hours. HCl37% (199 μl, 2.39 mmol) was added and the reaction mixture was warmedand stirred at 60° for 3 hours. The solvent was removed in vacuum. Theresidue was taken up with 25 mL sat. NaHCO₃ and extracted with CH₂Cl₂(3×25 mL). The organic layers were dried over Na₂SO₄ and concentrated invacuum. The crude material was purified by flash chromatography (silicagel, 0% to 10% MeOH in CH₂Cl₂, at the end 7M NH₃ in MeOH was used) toafford(1R,5S,8S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-amineas an off-white powder (126 mg, 76% yield). MS (ES+) m/z: 209.1[(M+H)⁺].

General Procedure 1: Buchwald Coupling Reaction

To a solution of an intermediate 9, 15 or 20 in 1,4-dioxane was added1.1 equivalent of an intermediate 10. The reaction mixture was degasedand a palladium catalyst [eitherdibromo-bis-(tritert.-butyl)-phosphine-palladium (0.1 eq.CAS185812-86-6) or tri(dibenzylidenacetonne) dipalladium(0)CAS51364-51-3 in the presence of2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl CAS564483-19-8]and NaOtBu (2.1 eq.) were added. The reaction mixture was heated at 100°C. until completion of the reaction (usually between 2 and 8 hours) andconcentrated under vacuo. A purification was done either by columnchromatography or reverse phase preparative HPLC to afford the desiredproduct.

EXAMPLE 14-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-1) and(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine(10-5) was prepared 13 mg of the title compound as a white solid. MS(ES+) m/z: 506.2 [(M+H)⁺].

EXAMPLE 2

N-[(1R,5S,8S)-3-(2-chloro-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-1) and(1R,5S,8S)-3-(2-chloro-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-amine(10-6) was prepared 15 mg of the title compound as a white solid. MS(ES+) m/z: 472.1 [(M+H)⁺].

EXAMPLE 34-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-1) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 26 mg of the title compound as a white solid. MS(ES+) m/z: 453.2 [(M+H)⁺].

EXAMPLE 44-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole(9-1) and(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine (10-5) was prepared 40 mg of the title compound as a whitesolid. MS (ES+) m/z: 492.3 [(M+H)⁺].

EXAMPLE 54-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole(9-1) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 24 mg of the title compound as a white solid. MS(ES+) m/z: 439.3 [(M+H)⁺].

EXAMPLE 6

4-[4-(trifluoromethyl)phenyl]-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-2) and(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine(10-5) was prepared 12 mg of the title compound as a white solid. MS(ES+) m/z: 538.2 [(M+H)⁺].

EXAMPLE 7

4-[4-(trifluoromethyl)phenyl]-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

Using the general procedure 1, from2-bromo-4-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine(20-2) and(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine(10-5) was prepared 12 mg of the title compound as a white solid. MS(ES+) m/z: 552.2 [(M+H)⁺].

EXAMPLE 8N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-2) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 21 mg of the title compound as a white solid. MS(ES+) m/z: 484.2 [(M+H)⁺].

EXAMPLE 9N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

Using the general procedure 1, from2-bromo-4-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine(20-2) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 19 mg of the title compound as a white solid. MS(ES+) m/z: 499.2 [(M+H)⁺].

EXAMPLE 104-(3-fluoro-4-methyl-phenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3-fluoro-4-methyl-phenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-4) and(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine(10-5) was prepared 34 mg of the title compound as a white solid. MS(ES+) m/z: 502.2 [(M+H)⁺].

EXAMPLE 114-(3-fluoro-4-methyl-phenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3-fluoro-4-methyl-phenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-4) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 29 mg of the title compound as a white solid. MS(ES+) m/z: 449.2 [(M+H)⁺].

EXAMPLE 12N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine

Using the general procedure 1, from2-bromo-4-[4-(trifluoromethyl)phenyl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazole (9-2) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 35 mg of the title compound as a white solid. MS(ES+) m/z: 471.3 [(M+H)⁺].

EXAMPLE 13N-[(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluoro-4-methyl-phenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3-fluoro-4-methyl-phenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-4) and(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-3) was prepared 4 mg of the title compound as a white solid. MS(ES+) m/z: 469.2 [(M+H)⁺].

EXAMPLE 144-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-1) and(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-4) was prepared 29 mg of the title compound as a white solid. MS(ES+) m/z: 469.2 [(M+H)⁺].

EXAMPLE 154-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-1) and(1R,5S,8S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-10) was prepared 16 mg of the title compound as a white solid. MS(ES+) m/z: 443.2 [(M+H)⁺].

EXAMPLE 16

N-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-1) and (1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine (10-8) was prepared 12 mg of the title compound asa white solid. MS (ES+) m/z: 473.1 [(M+H)⁺].

EXAMPLE 17N-[(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-1) and(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-3) was prepared 4 mg of the title compound as a white solid. MS(ES+) m/z: 473.1 [(M+H)⁺].

EXAMPLE 184-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-1) and(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-9) was prepared 24 mg of the title compound as a white solid. MS(ES+) m/z: 469.2 [(M+H)⁺].

EXAMPLE 194-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-1) and(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-2) was prepared 9 mg of the title compound as a white solid. MS(ES+) m/z: 471.2 [(M+H)⁺].

EXAMPLE 204-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Step 1: Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-1) andtert-butyl(1R,5S,8S)-8-amino-3-azabicyclo[3.2.1]octane-3-carboxylate (commerciallyavailable) was prepared 130 mg of tert-butyl(1R,5S,8S)-8-[[4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]amino]-3-azabicyclo[3.2.1]octane-3-carboxylateas a white solid. MS (ES+) m/z: 461.2 [(M+H)⁺].

Step 2: In analogy to the preparation of intermediate 10-1 (step 2) fromtert-butyl(1R,5S,8S)-8-[[4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]amino]-3-azabicyclo[3.2.1]octane-3-carboxylate(128 mg, 0.278 mmol) in CH₂Cl₂ in the presence of TFA (475 mg, 0.321 mL,4.17 mmol),N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine(94 mg, 94%) was obtained as a light yellow oil and used directly in thenext step without further purification. MS (ES+) m/z: 361.2 [(M+H)⁺].

Step 3: To a solution ofN-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine(30 mg, 0.083 mmol) in NMP (1 mL) was added 5-chloro-3-methylpyridazine(10.7 mg, 0.083 mmol) and DIPEA (32.3 mg, 43.6 μL, 0.25 mmol). Thereaction mixture was heated at 110° C. for 4 hours, concentrated undervacuo before a purification by reverse phase preparative HPLC gave4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine(4 mg, 12%) as a white solid. MS (ES+) m/z: 453.2 [(M+H)⁺].

EXAMPLE 214-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-1) and (1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-amine (10-7) was prepared 7 mg of the title compound as awhite solid. MS (ES+) m/z: 468.2 [(M+H)⁺].

EXAMPLE 224-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine(20-1) and(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine(10-5) was prepared 6 mg of the title compound as a white solid. MS(ES+) m/z: 520.2 [(M+H)⁺].

EXAMPLE 234-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine(20-1) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 12 mg of the title compound as a white solid. MS(ES+) m/z: 467.2 [(M+H)⁺].

EXAMPLE 244-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine(20-1) and(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-4) was prepared 7 mg of the title compound as a white solid. MS(ES+) m/z: 483.2 [(M+H)⁺].

EXAMPLE 25N-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine(20-1) and(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-8) was prepared 4 mg of the title compound as a white solid. MS(ES+) m/z: 487.2 [(M+H)⁺].

EXAMPLE 264-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine(20-1) and(1R,5S,8S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-10) was prepared 5 mg of the title compound as a white solid. MS(ES+) m/z: 457.2 [(M+H)⁺].

EXAMPLE 274-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

Using the general procedure 1, from2-bromo-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine(20-1) and(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-9) was prepared 6 mg of the title compound as a white solid. MS(ES+) m/z: 483.2 [(M+H)⁺].

EXAMPLE 284-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine

In anlogy to example 20, from2-bromo-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepine(20-1) was prepared 6 mg of the title compound as a white solid. MS(ES+) m/z: 467.2 [(M+H)^(+].)

EXAMPLE 29N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-5) and(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine(10-5) was prepared 22 mg of the title compound as a white solid. MS(ES+) m/z: 524.0 [(M+H)⁺].

EXAMPLE 30N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-5) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 9 mg of the title compound as a white solid. MS(ES+) m/z: 471.2 [(M+H)⁺].

EXAMPLE 31N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-5) and(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-4) was prepared 10 mg of the title compound as a white solid. MS(ES+) m/z: 487.2 [(M+H)⁺].

EXAMPLE 32N-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-5) and(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-8) was prepared 22 mg of the title compound as a white solid. MS(ES+) m/z: 491.1 [(M+H)⁺].

EXAMPLE 33N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-5) and(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-9) was prepared 12 mg of the title compound as a white solid. MS(ES+) m/z: 487.2 [(M+H)⁺].

EXAMPLE 344-(3-fluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-6) and(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine(10-5) was prepared 20 mg of the title compound as a white solid. MS(ES+) m/z: 488.2 [(M+H)⁺].

EXAMPLE 354-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-6) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 14 mg of the title compound as a white solid. MS(ES+) m/z: 435.2 [(M+H)⁺].

EXAMPLE 364-(4-fluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-7) and(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine(10-5) was prepared 14 mg of the title compound as a white solid. MS(ES+) m/z: 488.2 [(M+H)⁺].

EXAMPLE 374-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-7) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 7 mg of the title compound as a white solid. MS(ES+) m/z: 435.2 [(M+H)⁺].

EXAMPLE 384-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-7) and(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-4) was prepared 11 mg of the title compound as a white solid. MS(ES+) m/z: 451.3 [(M+H)⁺].

EXAMPLE 394-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-7) and(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-amine(10-7) was prepared 7 mg of the title compound as a white solid. MS(ES+) m/z: 450.2 [(M+H)⁺].

EXAMPLE 404-(3,5-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,5-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-3) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 7 mg of the title compound as a white solid. MS(ES+) m/z: 453.2 [(M+H)⁺].

EXAMPLE 414-(3,5-difluorophenyl)-N-[1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,5-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-3) and(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine(10-5) was prepared 8 mg of the title compound as a white solid. MS(ES+) m/z: 506.2 [(M+H)⁺].

EXAMPLE 424-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-7) and(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-9) was prepared 9 mg of the title compound as a white solid. MS(ES+) m/z: 451.2 [(M+H)⁺].

EXAMPLE 43N-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-7) and(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-2) was prepared 9 mg of the title compound as a white solid. MS(ES+) m/z: 453.2 [(M+H)⁺].

EXAMPLE444-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-6) and(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-8) was prepared 12 mg of the title compound as a white solid. MS(ES+) m/z: 451.2 [(M+H)⁺].

EXAMPLE 45N-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-6) and(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-2) was prepared 8 mg of the title compound as a white solid. MS(ES+) m/z: 453.2 [(M+H)⁺].

EXAMPLE 464-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-6) and(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-amine(10-7) was prepared 36 mg of the title compound as a white solid. MS(ES+) m/z: 450.2 [(M+H)⁺].

EXAMPLE 474-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-6) and(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-4) was prepared 3 mg of the title compound as a white solid. MS(ES+) m/z: 451.2 [(M+H)⁺].

EXAMPLE 48N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine

Using the general procedure 1, from2-bromo-4-(2,3,4-trifluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole(9-3) and(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine(10-1) was prepared 40 mg of the title compound as a white solid. MS(ES+) m/z: 457.3 [(M+H)⁺].

EXAMPLE 494-(3,5-difluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(3,5-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-3) and (1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-amine (10-7) was prepared 6 mg of the title compound as awhite solid. MS (ES+) m/z: 468.2 [(M+H)⁺].

EXAMPLE 504-(4-methoxyphenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

Using the general procedure 1, from2-bromo-4-(4-methoxyphenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine(15-13) and(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-amine(10-5) was prepared 48 mg of the title compound as a white solid. MS(ES+) m/z: 500.2 [(M+H)⁺].

1. A compound of formula I

wherein R¹ is hydrogen, lower alkyl, lower alkyl substituted by halogen,halogen, lower alkoxy or lower alkoxy substituted by halogen; R¹ may bethe same or different, if n=2 or 3; n is 1, 2 or 3; m is 1, 2 or 3; Aris a five or six membered heteroaryl group, selected from

wherein R² is hydrogen, lower alkyl, lower alkyl substituted by halogen,halogen or lower alkoxy; R³ is hydrogen or halogen; -( )_(m)- is—(CH₂)_(m)— or pharmaceutically active acid addition salts thereof.
 2. Acompound of formula I-1 according to claim 1,

wherein R¹ is hydrogen, lower alkyl, lower alkyl substituted by halogen,halogen, lower alkoxy or lower alkoxy substituted by halogen; R¹ may bethe same or different, if n=2 or 3; n is 1, 2 or 3; m is 1, 2 or 3; R²is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen orlower alkoxy; -( )_(m)- is —(CH₂)_(m)- or a pharmaceutically active acidaddition salts thereof.
 3. A compound of formula I-1 according to claim2, which compounds are4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineN-[(1R,5S,8S)-3-(2-chloro-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine4-[4-(trifluoromethyl)phenyl]-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-[4-(trifluoromethyl)phenyl]-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine4-(3-fluoro-4-methyl-phenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amineN-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,5-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,5-difluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineor4-(4-methoxyphenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine.4. A compound of formula I-2 according to claim 1

wherein R¹ is hydrogen, lower alkyl, lower alkyl substituted by halogen,halogen, lower alkoxy or lower alkoxy substituted by halogen; R¹ may bethe same or different, if n=2 or 3; n is 1, 2 or 3; m is 1, 2 or 3; R²is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen orlower alkoxy; R³ is hydrogen or halogen; -( )_(m)- is —(CH₂)_(m)— or apharmaceutically active acid addition salts thereof.
 5. A compound offormula 1-2 according to claim 4,which compounds are4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amineN-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineN-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine4-(3-fluoro-4-methyl-phenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineN-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amineN-[(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluoro-4-methyl-phenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineN-[(1R,5S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amineN-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineN-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,5-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineN-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineN-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineorN-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine.6. A compound of formula 1-3 according to claim 1,

wherein R¹ is hydrogen, lower alkyl, lower alkyl substituted by halogen,halogen, lower alkoxy or lower alkoxy substituted by halogen; R¹ may bethe same or different, if n=2 or 3; n is 1, 2 or 3; m is 1, 2 or 3; R²is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen orlower alkoxy; -( )_(m)- is —(CH₂)_(m)- or a pharmaceutically active acidaddition salts thereof.
 7. A compound of formula I-3 according to claim6, which compounds areN-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineN-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amineN-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineN-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineor4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine.8. A compound of formula I-4 according to claim 1,

wherein R¹ is hydrogen, lower alkyl, lower alkyl substituted by halogen,halogen, lower alkoxy or lower alkoxy substituted by halogen; R¹ may bethe same or different, if n=2 or 3; n is 1, 2 or 3; m is 1, 2 or 3; -()_(m)- is —(CH₂)_(m)- or a pharmaceutically active acid addition saltsthereof.
 9. A compound of formula I-4 according to claim 8, whichcompounds are4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amineor4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine.10. A process for preparing a compound of formula I as defined in anyone of claims 1-9, which process comprises a) reacting a compound offormula 9

with a compound of formula 10

to a compound of formula I

wherein the substituents have the meaning as described in claim 1, and,if desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts;
 11. A compound according to any one ofclaims 1-9, whenever prepared by a process as claimed in claim
 10. 12. Amedicament containing one or more compounds as claimed in any one ofclaims 1-9 and pharmaceutically acceptable excipients.
 13. A medicamentaccording to claim 12 for the treatment of Alzheimer's disease, cerebralamyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis,Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica orDown syndrome.
 14. The use of a compound in any one of claims 1-9 forthe manufacture of medicaments for the treatment of Alzheimer's disease,cerebral amyloid angiopathy, hereditary cerebral hemorrhage withamyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementiapugilistica or Down syndrome.
 15. A compound according to any one ofclaims 1-9 for use as therapeutically active substance.
 16. The use of acompound in any one of claims 1-9 for the treatment of Alzheimer'sdisease, cerebral amyloid angiopathy, hereditary cerebral hemorrhagewith amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementiapugilistica or Down syndrome.
 17. A compound according to any one ofclaims 1-9 for the treatment of Alzheimer's disease, cerebral amyloidangiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type(HCHWA-D), multi-infarct dementia, dementia pugilistica or Downsyndrome.
 18. A method for the treatment of Alzheimer's disease,cerebral amyloid angiopathy, hereditary cerebral hemorrhage withamyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementiapugilistica or Down syndrome, which method comprises administering aneffective amount of a compound as defined in any one of claims 1-9. 19.The invention as hereinbefore described.